Benazepril affects integrin-linked kinase and smooth muscle α-actin expression in diabetic rat glomerulus and cultured mesangial cells
Benazepril affects integrin-linked kinase and smooth muscle α-actin expression in diabetic rat glomerulus and cultured mesangial cells
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贝那普利影响糖尿病大鼠肾小球和培养的系膜细胞中整合素连接激酶和平滑肌α-肌动蛋白的表达
DOI：
10.1186/1471-2369-15-135
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发表时间：
2014-08-20
期刊：
影响因子：
2.3
通讯作者：
Li, Ying
中科院分区：
文献类型：
--
作者：
Niu, Honglin;Nie, Lei;Li, Ying
背景资料：糖尿病肾病（DN）是慢性肾脏疾病的主要原因，并与心血管疾病的发病率和死亡率过高。血管紧张素转换酶抑制剂（ACEI）苯那普利已被证明可以减缓慢性肾脏疾病的进展，并对慢性肾脏疾病和心血管疾病合并的患者具有有益作用。转化生长因子-β（1）（TGF-β（1））在DN的发病机制和进展中起核心作用。整合素连接激酶（ILK）可调节TGF-β 1诱导的肾小球系膜细胞（GMC）损伤，这是肾脏疾病的一个显著病理特征。作为整合素细胞质结合蛋白，ILK调节纤维连接蛋白（FN）基质沉积和肌动蛋白细胞骨架。平滑肌α-肌动蛋白（α-SMA）参与了人类和实验性肾脏疾病的进行性肾功能障碍。方法：采用实时荧光定量RT-PCR和蛋白质印迹法检测高糖（HG）诱导的肾小球系膜细胞（GMC）和链脲佐菌素（STZ）诱导的糖尿病大鼠肾脏TGF-β 1、ILK和α-SMA的表达，探讨苯那普利对肾脏保护作用的机制。为了阐明苯那普利对GMC细胞过程的作用机制，我们采用蛋白质印迹法检测了苯那普利对血管紧张素II（Angiotensin II，Ang II）信号通路的影响。结果：糖尿病组TGF-β 1、ILK和α-SMA的表达较对照组显著增加。贝那普利治疗抑制了DN中这些基因的表达，但未能挽救对照组中相同的水平。在HG或苯那普利处理的GMC中发现类似的结果。Ang II可增加HG组ERK和Akt的磷酸化，苯那普利不能完全阻断这些反应，提示其他分子可能参与DN的进展。我们的研究结果表明，苯那普利降低ILK和α-SMA的表达，至少部分是通过影响Ang II和TGF-β（1）之间的相互作用。结论：这里描述的研究结果支持糖尿病的HG环境增加TGF-β（1）分泌的假设，这增加了参与DN进展的ILK和α-SMA的合成。这可能是苯那普利在DN发病中发挥肾脏保护作用的重要机制。
Background: Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and is associated with excessive cardiovascular morbidity and mortality. The angiotensin converting enzyme inhibitor (ACEI) benazepril has been shown to slow the progression of chronic renal disease and have beneficial effects in patients with a combination of chronic renal disease and cardiovascular disease. Transforming growth factor-beta(1) (TGF-beta(1)) plays a central role in the pathogenesis and progression of DN. Integrin-linked kinase (ILK) can modulate TGF-beta(1)-induced glomerular mesangial cell (GMC) injury, which is a prominent characteristic of renal pathology in kidney diseases. As an integrin cytoplasmic-binding protein, ILK regulates fibronectin (FN) matrix deposition and the actin cytoskeleton. Smooth muscle alpha-actin (alpha-SMA) is involved in progressive renal dysfunction in both human and experimental renal disease.Methods: To explore the mechanisms of benazepril's reno-protective effects, we examined the expression of TGF-beta(1), ILK, and alpha-SMA in GMC exposed to high glucose (HG) and in the kidneys of streptozotocin (STZ)-induced diabetic rats using real-time quantitative RT-PCR and western blot analysis. To elucidate the mechanism(s) of the effect of benazepril on GMC cellular processes, we assessed the effect of benazepril on Angiotensin II (Ang II) signalling pathways using western blot analysis.Results: The expression of TGF-beta(1), ILK, and alpha-SMA increased significantly in the diabetic group compared with the control group. Benazepril treatment inhibited the expression of these genes in DN but failed to rescue the same levels in the control group. Similar results were found in GMC treated with HG or benazepril. Ang II increased ERK and Akt phosphorylation in the HG group, and benazepril could not completely block these responses, suggesting that other molecules might be involved in the progression of DN. Our findings suggest that benazepril decreases ILK and alpha-SMA expression, at least in part, by affecting the interactions between Ang II and TGF-beta(1).Conclusions: The findings described here support the hypothesis that the HG milieu of diabetes increases TGF-beta(1) secretion, which increases the synthesis of ILK and alpha-SMA that are involved in the progression of DN. This might be an important mechanism of the benazepril renal-protective function in the pathogenesis of DN.